Treatment for early stages of head and neck cancer has become more successful; however, the development of second primary tumors (SPTs) in patients surviving after treatment of their initial disease is becoming increasingly common. SPTs occur at a rate of 3 to 4% per year in patients who were previously treated for early stage (I, II) tumors. The development of SPTs in the aerodigestive tract region may be due to "field cancerization" by exogenous carcinogenic factors which affect the entire aerodigestive tract. It is well established that Retinoids and Carotenoids can inhibit and reverse carcinogen-induced preneoplastic lesions in epithelial organ culture and can suppress carcinoma development in carcinogen-treated animals. To decrease development of SPTs using the chemopreventive approach, we developed and conducted a controlled, double-blind, randomized trial of 13-cis retinoic acid (13-cRA) 50-100 mg/m2 daily vs. placebo in patients who were treated for squamous carcinoma of the head and neck. A total of 103 patients were enrolled in this study. At a median follow-up of 32 months, 13-cRA treatment had significantly reduced the incidence of second primary tumors (4% [2/49] vs. 24% [12/51], p = 0.005) and significantly increased the time to occurrence of a second primary (p=0.007), to yield a placebo: retinoid relative hazard of 5.59. The major problem encountered in this study was toxicity from high-dose 13-cRA. Based on this experience, we now propose a study using long-term treatment with low-dose 13-cRA to prevent SPTs in patients with early stages of head and neck cancer. This is a randomized, double-blind, placebo-controlled study of 13-cRA 30 mg. p.o. daily for the first year and then 15 mg. p.o. daily for the second and third years. A total of 1080 eligible patients will be recruited. Specific aims of this project are: a) to test the efficacy of low-dose 13-cRA for long-term treatment in reducing second primary tumors (SPTs) in patients who have been cured of head and neck cancer by surgery and/or radiotherapy; and b) to evaluate the qualitative and quantitative toxicity of low-dose 13-cRA administered daily. The overall objective of this project is to establish whether low-dose 13-cRA for long-term treatment will be a useful chemopreventive agent for aerodigestive tract epithelial cancer.